1. Field of the Invention
The invention relates to a process for electrophilically substituting thiazolidines or oxazolidines. The process is especially suitable for diastereoselectively electrophilically substituting thiazolidines or oxazolidines.
2. The Prior Art
The electrophilic α-functionalization of thiazolidines or oxazolidines, each of which are oxycarbonyl-functionalized in the 4-position, is a known synthetic strategy for α-functionalizing amino acids. The process is especially suitable for preparing α-functionalized, enantiomerically pure, unnatural amino acids.
It is known that compounds of the general formula (1) can be obtained, for example, by reacting the esters or the free acids (R1 may quite generally be hydrogen, a silyl or an organic radical) of the amino acids cysteine and serine (X is S or O) in the course of a condensation reaction with an aldehyde R2—CHO (R2 is an organic radical) and subsequent introduction of an amino protecting group P. The thiazolidine or oxazolidine derivatives prepared in this way may subsequently be further modified by introducing an electrophilic radical E into the 4-position by deprotonation and subsequent electrophilic substitution to obtain compounds of the general formula (2):

When the natural amino acids L-cysteine and L-serine or their unnatural D forms and a suitable R2 radical are selected to prepare the thiazolidine or oxazolidine derivatives of the general formula (1), the electrophilic substitution on the possible enantiomers or diastereomers resulting from two chiral centers in the 2- and in the 4-position of the heterocycle proceeds diastereoselectively in the 4-position and the compounds of the general formula (2) are obtained in the form of their pure optical isomers. This is illustrated by way of example in the form of the optical isomers of the general formulae (1a) and (2a) which are obtainable from the L forms of the amino acids cysteine and serine:

Final hydrolytic cleavage of compounds of the general formula (2) leads to α-substituted amino acid derivatives or their amine hydro salts of the general formula (4):

Depending on the R2 radical and prior diastereoselective reaction control, enantiomerically pure α-substituted cysteine or serine derivatives (4a) result, as illustrated here by way of example for one possible optical configuration.

As unnatural α-substituted amino acids, the enantiomerically pure or impure amino acid derivatives obtained by this general principle are valuable intermediates for the further conversion to various pharmaceuticals.
In the prior art, a series of processes have been described for the electrophilic substitution in the 4-position of compounds of the general formula (1), especially for the special case of methylation in the 4-position of the thiazolidine (X═S) or oxazolidine (X═O) which derive from cysteine methyl ester and serine methyl ester respectively, in which R2 is a tert-butyl radical and P is a formyl group.
For instance, D. Seebach et al. (Tetrahedron Lett. 1984, 25, 2545–2548, Helv. Chim. Acta 1987, 70, 1194–1216) describe the preparation of enantiomerically pure L-2-methylserine by alkylating the corresponding oxazolidine with methyl iodide. In this method, a solution of lithium diisopropylamide in THF/hexane with optional addition of hexamethylphosphoramide (HMPA) is initially charged at −78° C., and to this solution are added the oxazolidine and, after a further 10 min at −78° C., the electrophile methyl iodide. Within 12 h, the mixture is warmed to 0° C. and then worked up.
The methylation of corresponding thiazolidines with methyl iodide has been described in the preparation of enantiomerically pure L-/D-2-methylcysteine hydrochloride by G. Pattenden et al. (Tetrahedron 1993, 49(10), 2131–2138) and G. Mulqueen et al. (Tetrahedron 1993, 49(24), 5359–5364). Similar processes are also described in WO 01/72702 and WO 01/72703. In one possible variant, the thiazolidine is dissolved at −78° C. in THF with 1,3-dimethyltetrahydro-2(1H)-pyrimidone (DMPU) as a cosolvent, lithium hexamethyldisilazide in THF is added, the electrophile methyl iodide is added at −78° C. and finally, after 4 h at −78° C., the mixture was warmed to room temperature and worked up.
In a further variant, LiCl is dissolved homogeneously in 1,2-dimethoxyethane and THF, the thiazolidine is added at −65° C. dissolved in THF, the electrophile methyl iodide is added, and the base lithium hexamethyldisilazide is subsequently added at −65° C. and reacted at −65° C. for 10 h, and the mixture is finally warmed to room temperature and worked up.
In a third variant, DMPU is added at −78° C. to a solution of lithium diisopropylamide in hexane/THF, cooled to −90° C., then the thiazolidine is added in THF, the electrophile methyl iodide is added at −90° C. and, after 2 h at −90° C., warmed to room temperature and worked up.
In these processes, maximum yields of pure product of 46–63% are obtained after chromatographic workup.
The prior art processes described for the laboratory scale have a series of disadvantages, especially for industrial scale reaction. For instance, the use of extremely low temperatures cannot be realized on the industrial scale or is associated with disproportionately high costs.
The low reaction temperatures subsequently lead to uneconomically long reaction times and to a low solubility of the reactants in the solvents used, which in turn requires the use of large amounts of solvent and ultimately has a negative effect on the space-time yield.
The addition of cosolvents or lithium salts, which are used only as additives and consequently do not occur in the product, causes additional costs, and the auxiliaries also have to be removed again completely from the product in additional workup steps, in order to satisfy the high purity requirements on pharmaceutical intermediates.
The prior art electrophilic substitution processes of compounds of the general formula (1) for the preparation of unnatural, α-substituted amino acids of the general formula (4) consequently have a series of disadvantages which make scale-up from the laboratory scale to the industrial scale reaction uneconomic and inefficient.